Ankylosing spondylitis (AS) is a polygenic inflammatory disorder of the spine and extremities with potential for lifelong suffering. The histocompatibility allele HLA-B27 (B27) confers an odds ratio of 50 for susceptibility to AS and accounts for about 20% of the genetic risk. The cytokine pathway characterized by IL-17 has been shown to be central to the pathogenesis of AS and many other chronic inflammatory conditions. IL-23 is a key cytokine that drives chronic inflammation, and cells that produce IL-17 and cause chronic inflammation express receptors for IL-23 (IL23R+ cells). There are several different classes of such cells, but it is not known which one(s) are important in causing AS. Studies in mice genetically manipulated so that IL23R+ cells can be conveniently detected in vivo or in vitro by fluorescence have been extremely useful in characterizing the IL-23/IL-17 pathway in many different experimental disease systems. There is no good mouse model for AS. However, rats transgenic for HLA-B27 and human ?2-microglobulin (B27/ h?2m TG rats) develop an AS-like disease (spondyloarthritis), and this rat disease has been shown to be dependent upon IL-17 and to share a number of other features with human AS. In this Exploratory/Developmental Research Proposal, we plan to produce a genetically manipulated rat line in which cells expressing the IL- 23 receptor contain a fluorescent marker. Once the correct functioning of the fluorescent IL23R reporter is validated, we will then breed these rats with B27/ h?2m TG rats. Offspring carrying all three genes will be studied for development of spondyloarthritis. The fluorescent IL23R+ cells will be identified and isolated from lymphoid tissue and from the sites of pathology, and they will be characterized by flow cytometry for their cell surface markers, by RNA methods for their gene expression profiles, and by in vitro assays of their cytokine production. These studies should provide new and accurate information regarding the specific cell types that mediate the chronic inflammation of spondyloarthritis. This experimental system can then be used to identify potential therapeutic targets, and the IL23R reporter rats can be made available for studies of other disease processes. Our goal will be to continue with studies to determine the specific molecular role of HLA-B27 in activating the IL23R+ cells, through which we hope to finally identify the specific role of HLA-B27 in causing rheumatic disease.